Azarga 10mg/ml + 5mg/ml eye drops, suspension

The MAH has changed from adress has been updated to a Irish adress the MAholder remains the same

 

 

- Update to SmPC following approval of a CCDS submitted by Alcon and the Change of Ownership from Alcon to Novartis.

- SPC updated in line with CCSI version 4 changes with the addition of IMB name change to HPRA.

Variation to align with CCSI changes.

Most sections have been revised following the renewal of the licence and the type II variation approval to align with the QRD template and the Company Core Safety Information.

MAH address updated

.2       Posology and method of administration

 

Use in adults, including the elderly

The dose is one drop of AZARGA in the conjunctival sac of the affected eye(s) twice daily.

 

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.

 

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart.

 

If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye (s) twice daily.

 

When substituting another ophthalmic antiglaucoma agent with AZARGA, the other agent should be discontinued and AZARGA should be started the following day.

 

Paediatric patients

AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

 

Use in hepatic and renal impairment

No studies have been conducted with AZARGA or with timolol 5 mg/ml eye drops in patients with hepatic or renal impairment. No dosage adjustment is necessary in patients with hepatic impairment or in patients with mild to moderate renal impairment.

 

AZARGA has not been studied in patients with severe renal impairment (creatinine clearance <30 ml/min) or in patients with hyperchloraemic acidosis. Since brinzolamide and its main metabolite are excreted predominantly by the kidney, AZARGA is therefore contraindicated in patients with severe renal impairment (see section 4.3).

 

Method of administration

For ocular use.

 

Instruct patients to shake the bottle well before use.

 

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle.  Instruct patients to keep the bottle tightly closed when not in use.

4.3     Contraindications

 

·         Hypersensitivity to the active substances, or to any of the excipients.

·         Hypersensitivity to other beta‑blockers.

• Hypersensitivity to sulphonamides (see section 4.4).
• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.
• Severe allergic rhinitis and bronchial hyperreactivity; hypersensitivity to other beta‑blockers.
• Hyperchloraemic acidosis (see section 4.2).
• Severe renal impairment.
• Hypersensitivity to sulphonamides (see section 4.4).

 

4.4     Special warnings and precautions for use

 

Systemic effects

Like other topically applied ophthalmic agents, brinzolamide and timolol are absorbed systemically. Due to the beta‑adrenergic component, timolol, the same types of cardiovascular, and pulmonary and other adverse reactions as seen with systemic beta‑adrenergic blocking agents may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

 

Cardiac failure should be adequately controlled before beginning therapy with timolol. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failure, have been reported following administration of timolol maleate. Beta‑adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile insulin‑dependent diabetes as beta‑adrenergic blocking agents may mask the signs and symptoms of acute hypoglycaemia. They may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.

 

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.

 

Vascular disorders

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.

 

Beta-blockers may also mask the signs of hyperthyroidism.

 

Respiratory disorders

Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.

 

AZARGA should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

 

Hypoglycaemia/diabetes

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

 

Acid/base disturbances

AZARGA contains brinzolamide, a sulphonamide. The same types of undesirable effects that are attributable to sulphonamides may occur with topical administration. Acid‑base disturbances have been reported with oral carbonic anhydrase inhibitors. If signs of serious reactions or hypersensitivity occur, discontinue the use of this medicinal product.

 

 

There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitant administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5).

 

Mental alertness

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination in elderly patients. AZARGA is absorbed systemically and therefore this may occur with topical administration.

 

Anaphylactic reactions

While taking beta‑adrenergic blocking agentsblockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsivemore reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

 

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

 

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

 

Concomitant therapy

Timolol may interact with other medicinal products (see section 4.5).

 

The effect on intraocular pressure or the known effects of systemic beta blockade may be potentiated when AZARGA is given to patients already receiving an oral beta‑adrenergic blocking agent. The use of two local beta‑adrenergic blocking agents or two local carbonic anhydrase inhibitors is not recommended.

The effect on intra-ocular pressure or the known effects of systemic beta‑blockade may be potentiated when timolol is given to the patients already receiving a systemic beta‑blocking agent. The response of these patients should be closely observed. The use of two topical beta‑adrenergic blocking agents or two local carbonic anhydrase inhibitors is not recommended (see section 4.5).

 

There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitant administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5).

 

Ocular effects

There is limited experience with AZARGA in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and close monitoring of IOP is recommended.

 

AZARGA has not been studied in patients with narrow‑angle glaucoma and its use is not recommended in these patients.

 

Ophthalmic β-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

 

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination in elderly patients. AZARGA is absorbed systemically and therefore this may occur with topical administration.

 

The possible role of brinzolamide on corneal endothelial function has not been investigated in patients with compromised corneas (particularly in patients with low endothelial cell count). Specifically, patients wearing contact lenses have not been studied and careful monitoring of these patients when using brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydration and wearing contact lenses might increase the risk for the cornea. Careful monitoring of patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies, is recommended.

 

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since AZARGA contains benzalkonium chloride, close monitoring is required with frequent or prolonged use

 

AZARGA contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses is to be avoided. Patients must be instructed to remove contact lenses prior to the application of AZARGA and wait 15 minutes after instillation of the dose before reinsertion.

 

4.5         Interaction with other medicinal products and other forms of interaction

 

No specific drug interaction studies have been performed with AZARGA.

 

AZARGA contains brinzolamide, a carbonic anhydrase inhibitor and, although administered topically, is absorbed systemically. Acid‑base disturbances have been reported with oral carbonic anhydrase inhibitors. The potential for interactions must be considered in patients receiving AZARGA.

 

The cytochrome P‑450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. It is expected that inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamide by CYP3A4.  Caution is advised if CYP3A4 inhibitors are given concomitantly. However, accumulation of brinzolamide is unlikely as renal elimination is the major route. Brinzolamide is not an inhibitor of cytochrome P‑450 isozymes.

 

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when eye drops with timolol are administered concomitantly with oral calcium channel blockers, guanethidine or beta‑blocking agents, antiarrhythmics, digitalis glycosides or parasympathomimetics. There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.

 

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta‑blockers.

 

Potentiated systemic beta‑blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, cimetidinefluoxetine, paroxetine) and timolol.

 

Beta‑blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta‑blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

 

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

 

4.6         Fertility, Pregnancy and lactation

 

Pregnancy

There are no adequate data from the use of brinzolamide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).  The potential risk for humans is unknown. 

 

Well‑controlled epidemiological studies with systemic use of beta‑blockers did not indicate malformative effects, but some pharmacological effects such as bradycardia have been observed in foetuses or neonates. Data on a limited number of exposed pregnancies indicate no adverse effects of timolol in eye drops on pregnancy or on the health of the foetus/newborn child but bradycardia and arrhythmia have been reported in one case in the foetus of a woman treated with timolol eye drops. To date, no other relevant epidemiological data are available.

 

AZARGA should not be used during pregnancy unless clearly necessary.

Pregnancy

There are no adequate data for the use of brinzolamide or timolol in pregnant women. Azarga should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.

 

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If AZARGA is administered until delivery, the neonate should be carefully monitored during the first days of life.

 

Lactation

It is not known whether brinzolamide is excreted in human breast milk. Animal studies have shown excretion of brinzolamide in breast milk. Timolol does appear in human breast milk.  However, at therapeutic doses of AZARGA, no effects on the breastfed newborns/infants are anticipated. AZARGA can be used during breast‑feeding.

 

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2.

 

Fertility

 

Non clinical data do not show any effects of either brinzolamide or timolol on male or female fertility. No effects on male or female fertility are anticipated from the use of AZARGA.

4.5         Undesirable effects

 

Summary of the safety profile

In two clinical trials of 6 and 12 months duration involving 394 patients treated with AZARGA, the most frequently reported adverse reaction was transient blurred vision upon instillation (3.6%), lasting from a few seconds to a few minutes.

 

Tabulated summary of adverse reactions

The following adverse reactions are classified according to the following convention: very common (≥1/10), common≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), or very rare (<1/10,000), or not known (cannot be estimated from the available data).  Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

 

System Organ Classification	MedDRA Preferred Term
Psychiatric disorders	Uncommon: insomnia Not known: depression
Nervous system disorders	Common: dysgeusia
Eye disorders	Common: blurred vision, eye pain, eye irritation, foreign body sensation in eyes Uncommon: corneal erosion, punctate keratitis, dry eye, eye discharge, eye pruritus, ocular hyperaemia, blepharitis, allergic conjunctivitis, corneal disorder, anterior chamber flare, conjunctival hyperaemia, eyelid margin crusting, astenopia, abnormal sensation in eye, eyelids pruritus, allergic blepharitis, erythema of eyelid
Vascular disorders	Uncommon: decreased blood pressure
Respiratory, thoracic and mediastinal disorders	Uncommon: chronic obstructive pulmonary disease, pharyngolaryngeal pain, rhinorrhoea, cough
Skin and subcutaneous tissue disorders	Uncommon: hair disorder, lichen planus

 

Description of selected adverse reactions

Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reported systemic adverse reaction associated with the use of AZARGA during clinical trials. It is likely to be caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable to brinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the occurrence of this effect (see section 4.2).

 

AZARGA contains brinzolamide which is a sulphonamide inhibitor of carbonic anhydrase with systemic absorption. Gastrointestinal, nervous system, haematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. The same type of adverse reactions  attributable to oral carbonic anhydrase inhibitors may occur with topical administration.

 

AZARGA contains brinzolamide and timolol (as timolol maleate). Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. Additional adverse reactions associated with the use of the individual components observed in clinical trials and postmarketing experience that may potentially occur with AZARGA include those detailed below:. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see 4.2.

 

	Brinzolamide 10 mg/ml	Timolol 5 mg/ml
System Organ Classification	MedDRA Preferred Term
Infections and infestations	nasopharyngitis, pharyngitis, sinusitis, rhinitis
Blood and lymphatic system disorders	decreased red blood cell count, increased blood chloride
Immune system disorders:	hypersensitivity	Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylaxis
Metabolism and nutrition disorders		hypoglycaemia
Psychiatric disorders	apathy, depression, depressed mood, decreased libido, nightmare, nervousness	depressionNightmares, memory loss
Nervous system disorders	somnolence, motor dysfunction, amnesia, memory impairment, dizziness, paraesthesia, tremor, headache, hypoaesthesia, ageusia	cerebral ischaemia, cerebrovascular accident, syncope, increases in the signs and symptoms of myasthenia gravis, paresthesia, headache, dizziness
Eye disorders	keratitis, keratopathy, increased optic nerve cup/disc ratio, corneal epithelium defect, corneal epithelium disorder, increased intraocular pressure, eye deposit, corneal staining, corneal oedema, conjunctivitis, meibomianitis, diplopia, glare, photophobia, photopsia, reduced visual acuity, pterygium, ocular discomfort, keratoconjunctivitis sicca, hypoaesthesia of the eye, scleral pigmentation, subconjunctival cyst, increased lacrimation, visual disturbance, eye swelling, eye allergy, madarosis, eyelid disorder, eyelid oedema	conjunctivitis, diplopia, eyelid ptosis, keratitis, visual disturbance Signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), keratitis, choroidal detachment following filtration surgery (see section 4.4 Special warnings and precautions for use), decreased corneal sensitivity, ptosis, diplopia
Ear and labyrinth disorders	tinnitus, vertigo
Cardiac disorders	cardio‑respiratory distress, angina pectoris, bradycardia, irregular heart rate, arrhythmia, palpitations, tachycardia, increased heart rate	cardiac arrest, cardiac failure, arrhythmia, atrioventricular block, bradycardia, palpitations Bradycardia, chest pain, palpitations, oedema, arrhythmia, congestive heart failure, atrioventricular block, cardiac arrest, cardiac failure
Vascular disorders	increased blood pressure, hypertension	hHypotension  , Raynaud’s phenomenon, cold hands and feet
Respiratory, thoracic and mediastinal disorders	dyspnoea, asthma, bronchial hyperactivity, epistaxis, throat irritation, nasal congestion, upper respiratory tract congestion, postnasal drip, sneezing, nasal dryness	respiratory failure, bronchospasm, dyspnoea, nasal congestion Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), dyspnoea
Gastrointestinal disorders	dry mouth, oesophagitis, vomiting, diarrhoea, nausea, dyspepsia, upper abdominal pain, abdominal discomfort, stomach discomfort, frequent bowel movements, gastrointestinal disorder, oral hypoaesthesia, oral paraesthesia, flatulence	diarrhoea, nausea Nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain vomiting
Hepato-biliary disorders	abnormal liver function test
Skin and subcutaneous tissue disorders	urticaria, maculo‑papular rash, rash, generalised pruritus, alopecia, skin tightness, dermatitis, erythema	Aalopecia, rash Psoriasiform rash or exacerbation of psoriasis, skin rash
Musculoskeletal and connective tissue disorders	back pain, muscle spasms, myalgia, arthralgia, pain in extremity	Myalgia
Renal and urinary disorders	renal pain, pollakiuria
Reproductive system and breast disorders	erectile dysfunction	Sexual dysfunction, decreased libido
General disorders and administrative site conditions	pain, asthenia, chest discomfort, fatigue, feeling abnormal, feeling jittery, irritability, chest pain, peripheral oedema, malaise, medication residue	Asthenia/fatigue, chest pain
Injury, poisoning and procedural complications	foreign body in eye

 

 

Paediatric population

AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

10.    DATE OF REVISION OF THE TEXT

 

Detailed information on this medicine is available on the European Medicines Agency (EMEA) website: http://www.ema.europa.eu

17 February 2012

Amendement of Sec 10 (date of last revision of text has been added, this was missing from previous version of the SPC).